Cardiogenic shock trajectories: is the Society for Cardiovascular Angiography and Interventions definition the right one?

PURPOSE OF REVIEW: We review the current Society for Cardiovascular Angiography and Interventions (SCAI) cardiogenic shock classification system and consider alternatives or iterations that may enhance our current descriptions of cardiogenic shock trajectory. RECENT FINDINGS: Several studies have identified the potential prognostic value of serial SCAI stage re-assessment, usually within the first 24 h of shock onset, to predict deterioration and clinical outcomes across shock causes. In parallel, numerous registry-based analyses support the utility of a more precise assessment of the macrocirculation and microcirculation, leveraging invasive haemodynamics, imaging and additional laboratory and clinical markers. The emergence of machine learning and artificial intelligence capabilities offers the opportunity to integrate multimodal data into high fidelity, real-time metrics to more precisely define trajectory and inform our therapeutic decision making. SUMMARY: Whilst the SCAI staging system remains a pivotal tool in cardiogenic shock assessment, communication and reassessment, it is vital that the sophistication with which we measure and assess shock trajectory evolves in parallel our understanding of the complexity and variability of clinical course and clinical outcomes.

Exercise-Dependent Modulation of Immunological Response Pathways in Endurance Athletes With and Without Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia characterized by uncoordinated atrial electrical activity. Lone AF occurs in the absence of traditional risk factors and is frequently observed in male endurance athletes, who face a 2- to 5-fold higher risk of AF compared with healthy, moderately active males. Our understanding of how endurance exercise contributes to the pathophysiology of lone AF remains limited. This study aimed to characterize the circulating protein fluctuations during high-intensity exercise as well as explore potential biomarkers of exercise-associated AF. METHODS AND RESULTS: A prospective cohort of 12 male endurance cyclists between the ages of 40 and 65 years, 6 of whom had a history of exercise-associated AF, were recruited to participate using a convenience sampling method. The circulating proteome was subsequently analyzed using multiplex immunoassays and aptamer-based proteomics before, during, and after an acute high-intensity endurance exercise bout to assess temporality and identify potential markers of AF. The endurance exercise bout resulted in significant alterations to proteins involved in immune modulation (eg, growth/differentiation factor 15), skeletal muscle metabolism (eg, α-actinin-2), cell death (eg, histones), and inflammation (eg, interleukin-6). Subjects with AF differed from those without, displaying modulation of proteins previously known to have associations with incident AF (eg, C-reactive protein, insulin-like growth factor-1, and angiopoietin-2), and also with proteins having no previous association (eg, tapasin-related protein and α2-Heremans-Schmid glycoprotein). CONCLUSIONS: These findings provide insights into the proteomic response to acute intense exercise, provide mechanistic insights into the pathophysiology behind AF in athletes, and identify targets for future study and validation.

Association of duration and intensity of exercise with phenotypic expression in hypertrophic cardiomyopathy.

OBJECTIVES: There is limited data regarding the impact of exercise on phenotypic expression in hypertrophic cardiomyopathy (HCM). We aimed to investigate whether such an association exists in a cohort of genotype-positive HCM patients. METHODS: In this cross-sectional study of genotype-positive HCM families, we used structured questionnaires to obtain data regarding intensity and duration of exercise of participants starting at the age of 10, as well as data regarding exercise recommendations and their impact on quality of life (QOL). The association of cumulative metabolic-equivalent hours of exercise at different ages with different measures of phenotypic expression (maximal wall thickness, left atrial diameter, extent of late gadolinium enhancement) was analyzed. RESULTS: The study included 109 patients from 55 families, including 43 male (39%) and 90 (83%) phenotype-positive. No association was identified between exercise duration or intensity with any of the phenotypic markers with the exception of greater cumulative exercise associated with younger age at presentation. Similar results were obtained when analysis was limited to exercise until the age of 20, until the age of 30 or only after 30. Among phenotype-positive patients, 89% recalled receiving recommendations regarding exercise restriction, 29% noted reduction in exercise level following such recommendations and 25% noted this having a significant impact on their QOL. CONCLUSION: We found no association between exercise intensity or duration and phenotypic expression in genotype-positive HCM patients. These findings are important for physician-patient discussions and support the recent trend towards more permissive exercise restrictions in HCM.

Exercise in hypertrophic cardiomyopathy: restrict or rethink.

The detailed physiological consequences of aerobic training, in patients with hypertrophic cardiomyopathy (HCM), are not well understood. In athletes and nonathletes with HCM, there are two hypothetical concerns with respect to exercise: exercise-related worsening of the phenotype (e.g., promoting hypertrophy and fibrosis) and/or triggering of arrhythmia. The former concern is unproven and animal studies suggest an opposite effect, where exercise has been shown to be protective. The main reason for exercise restriction in HCM is fear of exercise-induced arrhythmia. Although the safety of sports in HCM has been reviewed, even more recent data suggest a substantially lower risk for sudden cardiac death (SCD) in HCM than previously thought, and there is an ongoing debate about restrictions of exercise imposed on individuals with HCM. This review outlines the pathophysiology of HCM, the impact of acute and chronic exercise (and variations of exercise intensity, modality, and athletic phenotype) in HCM including changes in autonomic function, blood pressure, cardiac dimensions and function, and cardiac output, and the underlying mechanisms that may trigger exercise-induced lethal arrhythmias. It provides a critical evaluation of the evidence regarding risk of SCD in athletes and the potential benefits of targeted exercise prescription in adults with HCM. Finally, it provides considerations for personalized recommendations for sports participation based on the available data.

A Novel Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Biomarker-Anti-DSG2-Is Absent in Athletes With Right Ventricular Enlargement.

BACKGROUND: Right ventricular (RV) enlargement is common in endurance athletes. It is usually considered to be physiological, but it is possible that this remodelling is adverse, manifesting as a variant of arrhythmogenic right ventricular cardiomyopathy (ARVC), termed "exercise-induced ARVC." A novel biomarker (anti-desmoglein-2 [anti-DSG2] antibody) has been shown to indicate ARVC with high sensitivity and specificity and may be an immune response to breakdown of RV desmosomes. It is not known if this antibody is present in endurance athletes with RV enlargement but without clinical ARVC. METHODS: Middle-aged, healthy endurance athletes with RV enlargement on cardiac magnetic resonance imaging had serum tested for the presence of the anti-DSG2 antibody. All athletes also underwent Holter monitoring, a signal-averaged electrocardiogram, and an exercise questionnaire. RESULTS: A total of 30 athletes (20 men, 10 women, average age 53 ± 6 years) were enrolled in this study with median RV end-diastolic volume indexes of 117.1 mL/m2 (men) and 103.5 mL/m2 (women). Athletes demonstrated other characteristics of endurance training, including depolarization abnormalities (abnormal signal-averaged electrocardiogram, 19 of 30) and incomplete right bundle branch block (8 of 30). No athlete met criteria for definite or probable ARVC. None of the athletes tested positive for anti-DSG2 antibody. CONCLUSIONS: Among middle-aged endurance athletes with RV enlargement, the anti-DSG2 antibody, a suggested ARVC biomarker, is absent in all and is highly specific in this cohort (95% confidence interval, 88%-100%). Despite significant RV remodelling, these athletes did not express a previously characterized pathologic biomarker known to be sensitive for ARVC. Physiological exercise remodelling and pathologic ARVC remodelling are likely separate processes.

INTRODUCTION: L'augmentation du volume du ventricule droit (VD) est fréquente chez les sportifs d'endurance. On considère habituellement que ce remodelage est physiologique, mais il est possible qu'il soit indésirable, c'est-à-dire qu'il révèle une variante de la cardiomyopathie arythmogène du ventricule droit (CAVD), appelée « CAVD induite par l'exercice ¼. Il a été démontré qu'un nouveau biomarqueur (l'anticorps anti-desmogléine 2 [anti-DSG2]) présente une sensibilité et une spécificité élevées pour dépister la CAVD et qu'il peut être une réponse immunitaire à la dégradation des desmosomes du VD. On ne sait pas si cet anticorps est présent chez les sportifs d'endurance qui ont une augmentation du volume du VD, sans CAVD clinique. MÉTHODES: Les sportifs d'endurance d'âge moyen en bonne santé qui ont une augmentation du volume du VD à l'imagerie cardiaque par résonance magnétique ont subi une épreuve pour vérifier la présence de l'anticorps anti-DSG2 dans le sérum. Tous les athlètes ont également eu une surveillance par la méthode de Holter, un électrocardiogramme à signaux moyennés et un questionnaire sur l'exercice. RÉSULTATS: Nous avons inscrit à cette étude un total de 30 athlètes (20 hommes, 10 femmes, âge moyen de 53 ± 6 ans) dont les indices volumiques télédiastoliques médians du VD des hommes étaient de 117,1 ml/m2 et des femmes, de 103,5 ml/m2. Les athlètes ont démontré d'autres caractéristiques de l'entraînement en endurance, notamment des anomalies de la dépolarisation (électrocardiogramme à signaux moyennés anormal, 19 sur 30) et un bloc de branche droit incomplet (8 sur 30). Aucun athlète n'a répondu aux critères de CAVD définie ou probable. Aucun des athlètes n'a eu de résultats positifs au test de dépistage des anticorps anti-DSG2. CONCLUSIONS: Chez tous les sportifs d'endurance d'âge moyen qui ont une augmentation du volume du VD, l'anticorps anti-DSG2, un biomarqueur proposé pour dépister la CAVD, est absent et est hautement spécifique dans cette cohorte (intervalle de confiance à 95 %, 88 %-100 %). En dépit d'un remodelage important du VD, les athlètes n'ont pas exprimé le biomarqueur pathologique, auparavant caractérisé, connu pour être sensible au dépistage de la CAVD. Le remodelage physiologique induit par l'exercice et le remodelage pathologique associé à la CAVD sont des processus probablement distincts.

Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNFα, in exercised-induced atrial remodelling. Accordingly, exercise induces TNFα-dependent activation of both NFκB and p38MAPK, while TNFα inhibition (with etanercept), TNFα gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNFα as a key factor in the pathology of intense exercise-induced AF.

Exploring the role of miRNAs in renal cell carcinoma progression and metastasis through bioinformatic and experimental analyses.

Metastasis results in most of the cancer deaths in clear cell renal cell carcinoma (ccRCC). MicroRNAs (miRNAs) regulate many important cell functions and play important roles in tumor development, metastasis and progression. In our previous study, we identified a miRNA signature for metastatic RCC. In this study, we validated the top differentially expressed miRNAs on matched primary and metastatic ccRCC pairs by quantitative polymerase chain reaction. We performed bioinformatics analyses including target prediction and combinatorial analysis of previously reported miRNAs involved in tumour progression and metastasis. We also examined the co-expression of the miRNAs clusters and compared expression of intronic miRNAs and their host genes. We observed significant dysregulation between primary and metastatic tumours from the same patient. This indicates that, at least in part, the metastatic signature develops gradually during tumour progression. We identified metastasis-dysregulated miRNAs that can target a number of genes previously found to be involved in metastasis of kidney cancer as well as other malignancies. In addition, we found a negative correlation of expression of miR-126 and its target vascular endothelial growth factor (VEGF)-A. Cluster analysis showed that members of the same miRNA cluster follow the same expression pattern, suggesting the presence of a locus control regulation. We also observed a positive correlation of expression between intronic miRNAs and their host genes, thus revealing another potential control mechanism for miRNAs. Many of the significantly dysregulated miRNAs in metastatic ccRCC are highly conserved among species. Our analysis suggests that miRNAs are involved in ccRCC metastasis and may represent potential biomarkers.